A brief history of AIDS

Robert C Gallo, one of the co-discoverers of HIV, gives a personal and historical insight into 25 years of the disease

In 1981 newspaper stories started appearing about a collection of cases of unusual fungal and parasitic infections, especially Pneumocystis carinii, in the east coast of the United States. Articles followed about cases of the rare neoplasia known as Kaposi's sarcoma from the west coast in homosexual men. Strange though they were, these cases were not important or exciting enough to change your career. I was working on leukaemia at the National Cancer Institute in Bethesda, and the reports came at a tranquil and pleasant moment in my life.^1-3

Cliff Spicer/Features Photo Service/News.com

We had learnt how to grow T cells for the first time only five years earlier.^{4 5}This was based on our discovery of a growth factor activity for T cells now known as interleukin 2. In turn the ability to culture and replicate T cells coupled with sensitive specific assays for reverse transcriptase⁶⁷ led to our discovery of human T cell leukaemia/lymphoma virus type I (HTLV-1), one of the first identified viruses that causes cancer in humans.^8-10. Reverse transcriptase is a DNA polymerase, like the DNA polymerases in our cells. All catalyse the synthesis of DNA from a DNA template, but reverse transcriptase is special because it also transcribes RNA into DNA-a feat previously unknown in biology.¹¹¹² Because reverse transcriptase is found in all animal retroviruses and because tests for it could be made sensitive, fast, and specific, we adapted it as a surrogate marker in our search for a human retrovirus.

HTLV-1 causes a T cell leukaemia, usually of CD4 T cells, often in young adults.¹³ This was the first known leukaemia virus in humans, and the quest for it was long, controversial, and more difficult than finding HIV. By 1981 we knew that HTLV-1 was transmitted by blood, by sex, and from mother to infant, especially by breast feeding, and we knew it could impair immunity. In the same period of 1981 we found a second human retrovirus (HTLV-2).^{910 14} We were excited by this work and began to focus on how the virus caused leukaemia when the AIDS problem gained more significance because of increasing numbers and the mysteries surrounding it.

Finally, after listening to a lecture at the US National Institutes of Health by James Curran of the Centers for Disease Control and Prevention, the pioneering epidemiologist of AIDS, I was stimulated to think seriously about this problem. Led by Curran, the Centers for Disease Control and Prevention made the first reports on the original AIDS cases in their publication.

Here was a new disease, and Curran told us if it was because of an infectious agent then its transmission would likely be by blood (haemophiliacs and intravenous drug misusers were affected), sex, and mother to infant. Clinicians told us that it seemed that the main immune impairment involved CD4 T cells. All these things fitted with what we knew about human retroviruses. Moreover, AIDS seemed to be prevalent in Haiti and tropical Africa. These were places we knew HTLVs to be prevalent. Consequently, in 1982 along with Max Essex in Boston, I postulated that the cause of AIDS would likely be another human retrovirus, one I logically assumed would belong to the HTLV family. This idea was the only one that bore fruit. The cause of AIDS was indeed a new retrovirus, but one distinct from the HTLV family.

One milestone after another

We began our research in May 1982 by exploring T cells from patients with AIDS for HTLV related retroviruses using molecular probes and testing serums for antibodies. We also began culturing T cells from the blood of some patients with AIDS in an attempt to detect and then isolate a putative new retrovirus. In early 1983 we reported and described a few positive results, but because of looking for HTLV relatedness, these samples were always mixed with and dominated by HTLV. In other words, these were patients infected with both HTLV and HIV.¹⁵At the same time, Luc Montagnier and his colleagues in Paris reported detection of an unambiguously new retrovirus in a patient with lymph gland enlargement that later would be proved to be the AIDS virus.¹⁶

Our original problem was the mixture of retroviruses, whereas Montagnier's problem was the inability to sustain his strain of HIV in continuous culture. Neither group could at that time claim that its work showed that the viruses caused AIDS. That would happen exactly a year later, in 1984, when my colleagues and I were able to find HIV in 48 patients with AIDS or in people in so called AIDS risk groups.¹⁷ We were also able to continuously propagate the virus in cell line culture,¹⁸ a critical advance that led to early characterisation of HIV proteins¹⁹ and the development of the serum antibody based HIV blood test.^19-21 The blood test enabled us to screen hundreds and ultimately thousands of serums. Along with the many isolates of the virus,¹⁷ the evidence that it targeted CD4 T cells,¹⁶¹⁸ and the fact that like AIDS the virus was also new, as well as some other considerations²² led us to conclude that HIV was the cause of AIDS.

Of course, the blood test also had immense practical effects for the field. The blood supply used for medical purposes-for transfusions-could now be protected. The epidemic could be followed because no longer would we have to wait to see the signs of AIDS (usually needing some 5 to 15 years); now we could follow infection almost from the onset. Education programmes could be accelerated and individual patients advised. The systems developed for continuous cell line production of HIV also yielded practical beneficial results. They were used to test drugs against HIV, beginning another medical historic and dramatic aspect to the story, namely the first successful antiviral treatment. This began with zidovudine (azidothymidine, AZT),²³ and culminated in the triple drug therapy²⁴ now called HAART (highly active antiretroviral treatment) that was launched in the mid-1990s and developed by many groups.

Finding the cause of AIDS presented unusual challenges. Firstly, because the signs of disease were not seen until after a decade after infection it meant that the clues were scant. Secondly, the disease was usually associated with multiple opportunistic infections by the time it appeared. Which infection was the cause? In this respect the blood test was indispensable because it was safe to do, sensitive, specific, rapid, and inexpensive. This made it useful on a global scale.

Once the cause was established and all the necessary reagents made available-for example, virus cultures, HIV molecular probes, specific antibodies, and so on-the field exploded. Those early years of 1982-5 may represent the fastest pace ever achieved in medical science from the time of the birth of a new disease to advances in its understanding, diagnosis, prevention, and treatment. Additional advances in this earliest period included the finding of HIV related retroviruses in monkeys (simian immunodeficiency virus, SIV), the use of SIV in some monkeys to induce AIDS,^{25 26} and use of this model for experimental studies of pathogenesis and vaccine research.

At the same time that these tunes were filled with excitement as we watched the mysteries of the new epidemic all one by one, they were also filled with worries, stress, puzzlement, and frank confusion. Much of this, of course, was caused by a new mystery: how could we best take advantage of our knowledge about HIV to help end the epidemic? For example, how much should we virologists turn ourselves into vaccinologists? This question weighed on me especially, because I soon learnt that no one person or group was really responsible for developing a vaccine. Worse, the vaccinologists I spoke with were much too ill informed about the special characteristics of retroviruses.

The medical-scientific issues were, however, only a fraction of our concerns. Soon we would be dealing with patients' issues related to the blood test for HIV; facing lawyers and public relations firms; and enduring the wrath of activists, many of whom were patients. To my knowledge this was another historical first in medicine. The anger shown by activists towards scientists was partly to draw attention to the activists' cause. Their real anger was because of the impression that society as a whole, and government in particular, were not doing enough. Some of their anger towards us, however, was real. They saw the blood test as a "tattoo" that marked them at a time when prejudices were running high. Although they soon realised the necessity of the blood test and the great advances made possible by it, they were initially in a hopeless state with no treatment except the less than optimal options for secondary opportunistic infections. In the end, the activists became our greatest supporters and sometimes gave us new insights into the disease. Looking back, though, I realise how we physician-scientists are unprepared to deal with many issues, such as patients and lawyers, public relations and the media, and activists.

In those early days, we could anticipate many of the developments that occurred in the next 20 years. From our serological studies we knew from the start that AIDS would soon be global, but no one could have possibly anticipated the great African catastrophe. From its nature as a retrovirus we also knew that HIV infection would be life long for the patient and would not quickly go away, like most epidemics. HIV was here to stay unless abolished by scientific success with a preventive vaccine. We suspected that a successful vaccine against HIV would be exceptionally difficult to make, not only because of the virus's variability but even more importantly because of the capacity of a retrovirus to integrate its genetic information into its target cell within a few days (or less) from the time of infection. With this characteristic comes real trouble because it implies we may have to block infection completely and from the onset, and this has never been achieved with any vaccine before.

Treatment is another matter. I must confess I was pessimistic about the prospects of effectively treating HIV. Because viruses are so much a part of us, they provide few specific targets. Also retroviral infections are life long, thereby rendering any virological cure almost impossible. Consequently, treatment would need to be life long and would be accompanied by the toxicity and viral drug resistance problems that are likely to occur with decades of treatment. Some therapeutic successes were evident by the mid to late 1980s, however, and important advances in treatment would happen soon.

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A fascinating assassin

Putting science ahead

Almost 23 years have passed since we found the cause of AIDS. Almost all the important advances in HIV/AIDS research were made in the early period of 1982-5, which in turn led to every practical application that affects infected people. Surely subsequent work has been important and will be essential to the final solution-removing HIV from the human population.

Where are we today, and what are the major problems? HIV has killed about 30 million people and about 40 million are infected. My colleague, the epidemiologist William Blattner, likes to point out that the Indian Ocean tsunami of 2004 killed an estimated 230 000 people. HIV is akin to a tsunami killing more than 250 000 people every month. But can we expect things to improve? I believe this is impossible to predict because the epidemic is still in a dynamic state and because it is equally difficult to predict human behaviour or sustained governmental support. For example, if another attention grabbing calamity affects the globe, HIV may not be seen as so critical a problem.

And increasing number of HIV variants, including recombinant forms, may not behave like the earliest HIV strains in response to treatment and resistance to drugs. And this is not an infectious agent that is going to go away on its own. Retroviruses generally establish permanent or at least long lasting infections within a species. Conversely, I believe it is impossible for HIV to evolve into a casually transmissible virus. This would change its cellular tropism to such an extent that it would be unlikely it could still target critical cells of our immune system. Indeed, I know of no case of a retrovirus in any species that is casually transmitted.

The future depends in part on expanding blood testing and promoting education throughout the world. It also depends on distribution of the various anti-HIV drugs to people in need, and all depend upon sustained financing and commitment by many parts of society. The HIV/AIDS problem takes more than medical scientists and clinicians. It necessarily involves other social and healthcare workers and support groups. Nevertheless, I fear that their growing involvement could overshadow the paramount role that must be played by science. We have already seen this phenomenon occur at some of the large international AIDS meetings. This may also be aggravated by what I see as a growing gap between scientists and people not so engaged because of the increasing technical complexity of medical research.

We must never forget the essential role still to be played by medical science. We have effective treatment only because of the basic research into HIV. Because life long treatment is needed, drug resistance and toxicity occur, and this demands new forms of treatment, which in turn are forthcoming only from more research. So far science has managed to keep up with the virus, although a virological cure has not been attained, nor is one likely. The ultimate answer, of course, is a successful preventive vaccine. The difficulties in developing a vaccine for any retrovirus are formidable, and even more so for HIV because of its variability.²⁷ Causes for hope spring from the recent advances in our understanding of some of the details of HIV entry into the cell^28-34 and the structure of the HIV envelope.³⁵³⁶My current thoughts lean towards optimism. If we are correct, perhaps we can envisage that this will be the last time that a 25 year reflection is needed.

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